Process of a quaternary ammonium salt

ABSTRACT

The present invention relates to a novel process for preparing quaternary ammonium salt derivatives.

CROSS REFERENCE TO RELATED APPLICATION

This application is a utility application and claims the benefit of U.S.Provisional Application No. 61/327,809, filed Apr. 26, 2010 the completedisclosure of which is incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a process for preparing quaternaryammonium salt derivatives.

BACKGROUND ART

An imide derivative or a salt thereof whose typical example is acompound of formula (8) mentioned later or an acid addition salt thereofis known to be useful as a medicament for treating schizophrenia, senilepsychiatric disorder, bipolar disorder, neurosis, etc. (Patent Reference1). And, some processes for preparing an imide derivative of thefollowing formula (I):

wherein A is optionally substituted C₂₋₄ alkylene group or other, D iscarbonyl group or other, Y is optionally substituted C₁₋₂ alkylenegroup, Z is optionally substituted imino group or otherare also reported. For example, Patent Reference 2 discloses a processfor preparing the imide derivative of the above-mentioned formula (I)which comprises reacting a compound of formula (II):

wherein A is optionally substituted C₂₋₄ alkylene group or other, and Dis carbonyl group or other, and a quaternary ammonium salt of formula(III):

wherein Y is optionally substituted C₁₋₂ alkylene group, Z is optionallysubstituted imino group or other, X⁻ is a counteranionin the presence of a solid inorganic base and water.

In addition, Patent Reference 3 discloses that the compound of formula(III) can be prepared by reacting a compound of formula (IV):

wherein Z is optionally substituted imino group or other, anda compound of formula (V):

wherein X is a group which can become the above counteranion X⁻ aftercleavage, and Y is optionally-substituted C₁₋₂ alkylene group in thepresence of potassium carbonate whose specific surface area is less than1.8 m²/g.

Furthermore, Patent Reference 4 discloses a process for preparing thecompound of formula (III) which comprises reacting the compound offormula (IV) and the compound of formula (V) in an organic solvent inthe presence of potassium carbonate whose mean particle size (50% D) isnot more than 200 μm.

However, these processes have some problems on the preparing processes,for example, the product of formula (I) contains a by-product(hereinafter, referred to as “by-product (R)”), or the reaction time ofthe preparing processes is unstable. Such by-product (R) might cause thequality loss of the imide compound of formula (I), hence it is necessaryto remove the by-product through a purification. Thus, it has beendesired to further reduce the producing of by-product (R) and stabilizethe reaction time from the viewpoint of the yield of the product and theproduction cost.

PRIOR ART

[Patent Reference]

[Patent Reference 1] JP 2800953 B

[Patent Reference 2] JP 2003-160583 A

[Patent Reference 3] JP 2006-169155 A

[Patent Reference 4] JP 2006-169154 A

DISCLOSURE OF INVENTION Problem to be Solved by the Invention

Under the situation, the present inventors have extensively studied toreduce the producing of by-product (R) and then have found that thecause of producing by-product (R) is potassium carbonate which is usedin the reaction of compound (IV) and compound (V) as a base. And, theinventors have further extensively studied other bases instead ofpotassium carbonate which has been understood as an optimal base in thereaction process and then have found that the producing of by-product(R) can be reduced by using an excessive amount of the followingcompound of formula (3) instead of potassium carbonate in the reactionof the following compound of formula (1) and the compound of formula(3), and the improved process enable the reaction time to be stabilized.Based upon the new findings, the present invention has been completed.

Means to Solve the Problem

The present inventions are as follows.

Term 1:

A process for preparing a quaternary ammonium salt of formula (4):

wherein

X is halogen atom, C₁₋₆ alkylsulfonyloxy group, or C₆₋₁₀ arylsulfonyloxygroup, and X⁻ is a counteranion thereof,

Y is a substituent of the following formula (2a) or (2b):

wherein R¹ is independently methylene or oxygen atom; R² isindependently C₁₋₆ alkyl group, C₁₋₆ alkoxy group, or hydroxy group; mand n are independently 0, 1, 2, or 3; and p is 1 or 2, and

Z is ═N—R³ or —CH—R⁴ wherein R³ is C₁₋₆ alkyl group, C₃₋₇ cycloalkylgroup, C₅₋₇ cycloalkenyl group, C₆₋₁₀ aryl group, or 5- to 10-memberedmonocyclic or bicyclic heteroaryl group; R⁴ is C₁₋₆ alkyl group, C₁₋₆alkoxy group, C₁₋₆ alkylthio group, C₃₋₇ cycloalkyl group, C₃₋₇cycloalkyloxy group, C₃₋₇ cycloalkylthio group, C₅₋₇ cycloalkenyl group,C₅₋₇ cycloalkenyloxy group, C₅₋₇ cycloalkenylthio group, C₆₋₁₀ arylgroup, C₆₋₁₀ aryloxy group, C₆₋₁₀ arylthio group, 5- to 10-memberedmonocyclic or bicyclic heteroaryl group, 5- to 10-membered monocyclic orbicyclic heteroaryloxy group, or 5- to 10-membered monocyclic orbicyclic heteroarylthio group,

comprising reacting a compound of formula (1):

wherein X is independently selected from the above-defined ones, and Yis as defined above,

with 1.5 to 15 mole of a compound of formula (3):

wherein Z is as defined above, per one mole of the compound of formula(1)

to prepare the quaternary ammonium salt of formula (4).

Term 2:

The process of Term 1 wherein the reaction of Compound (1) with Compound(3) includes the following steps (i) and (ii):

step (i): reacting Compound (1) with 0.1 to 1.0 mole of compound (3) perone mole of Compound (1), and then

step (ii): adding the rest of Compound (3) to the reaction mixture sothat the total amount of Compound (3) can be 1.5 to 15 mole per one moleof Compound (1), and continuing the reaction.

Term 3:

The process of Term 1 wherein the reaction of Compound (1) with Compound(3) includes the following steps (i) and (ii):

step (i): reacting 0.1 to 1.0 mole of Compound (1) with 0.1 to 1.0 moleof Compound (3) per one mole of the total amount of compound (1), andthen

step (ii): adding the rest of Compound (1) and the rest of Compound (3)to the reaction mixture so that the total amount of Compound (3) can be1.5 to 15 mole per one mole of the total amount of Compound (1), andcontinuing the reaction.

Term 4:

The process of Term 2 or 3 wherein the reaction is carried out in thepresence of 0.1 to 1.0 mole of an inorganic salt per one mole of thetotal amount of Compound (1).

Term 5:

The process of Term 4 wherein the inorganic salt is potassium carbonate.

Term 6:

The process of Term 4 or 5 wherein the amount of an inorganic salt is0.1 to 0.3 mole per one mole of the total amount of Compound (1).

Term 7:

The process of any one of Terms 2 to 6 wherein the amount of Compound(3) added in step (i) is 0.1 to 0.5 mole per one mole of the totalamount of Compound (1).

Term 8:

The process of any one of Terms 2 to 7 wherein the total amount ofCompound (3) in step (ii) is 1.8 to 5 mole per one mole of Compound (1).

Term 9:

The process of any one of Terms 1 to 8 wherein X is independently C₁₋₆alkylsulfonyloxy group, or C₆₋₁₀ arylsulfonyloxy group.

Term 10:

The process of Term 9 wherein X is methanesulfonyloxy group.

Term 11:

The process of any one of Terms 1 to 10 wherein Y is the substituent offormula (2a).

Term 12:

The process of Term 11 wherein m is 2 and n is 0.

Term 13:

The process of any one of Terms 1 to 12 wherein Z is ═N—R³.

Term 14:

The process of Term 13 wherein R³ is 5- to 10-membered monocyclic orbicyclic heteroaryl group.

Term 15:

The process of term 14 wherein R³ is 1,2-benzisothiazol-3-yl.

Term 16:

The process of any one of Terms 1 to 8 wherein

the compound of formula (1) is

the compound of formula (3) is

and

the quaternary ammonium salt of formula (4) is

Term 17:

A process for preparing a compound of formula (8):

wherein

B is carbonyl group or sulfonyl group,

R^(5a), R^(5b), R^(5c), and R^(5d) are independenly hydrogen atom orC₁₋₄ alkyl group, alternatively R^(5a) and R^(5b), or R^(5a) and R^(5c)may be taken together to form a hydrocarbon ring, or R^(5a) and R^(5c)may be taken together to form an aromatic hydrocarbon ring, wherein thehydrocarbon ring may be bridged with C₁₋₄ alkylene or oxygen atomwherein the C₁₋₄ alkylene and the hydrocarbon ring may be substitutedwith at least one C₁₋₄ alkyl,

q is 0 or 1, and

Y and Z are as defined in term 1,

comprising reacting the quaternary ammonium salt (4) prepared accordingto any one of terms 1 to 16 with the following compound (7):

wherein B, R^(5a), R^(5b), R^(5c), R^(5d), and q are as defined above,in the presence of a solid inorganic base.Term 18:

The process of Term 17 wherein B is carbonyl group.

Term 19:

The process of Term 17 or 18 wherein R^(5a) and R^(5c) are takentogether to form a hydrocarbon ring which may be bridged with C₁₋₄alkylene, and R^(5b) and R^(5d) are hydrogen atom.

Term 20:

The process of Term 19 wherein Compound (7) is the following compound offormula (7b):

Term 21:

The process of any one of Terms 17 to 20 wherein Compound (8) is(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}-hexahydro-4,7-methano-2H-isoindole-1,3-dione.

Effect of the Invention

According to the present invention, in the process for preparing thequaternary ammonium salt of the above formula (4) (hereinafter,abbreviated as “quaternary ammonium salt (4)”), the reaction can be donewith a steady repeatability of the reaction time while the production ofby-product (R) can be held down. Furthermore, according to the presentinvention, the process for preparing the compound of formula (8) or anacid addition salt thereof which is known as a medicament for treatingschizophrenia or similar diseases, for example,(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-yl-methyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione(2-[[(1R,2R)-2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]methyl]cyclohexyl]methyl]hexahydro-(3aS,4R,7S,7aR)-4,7-methano-1H-isoindole-1,3(2H)-dione),can be done in high purity and high efficiency.

It is thought that the present invention can make the production ofby-product (R) held down and make the reaction time stabilized in themechanism mentioned below. Namely, the compound of formula (3)(hereinafter, abbreviated as “Compound (3)”) can be reacted with thecompound of formula (1) (hereinafter, abbreviated as “Compound (1)”) toprepare quaternary ammonium salt (4) while Compound (3) works as a basewith its internal amino group, and simultaneously the rest of Compound(3) forms a salt with “X” originated from Compound (1) to prepare thecompound of formula (5):

wherein X⁻ is the above-mentioned counteranion, and Z is as definedabove (hereinafter, abbreviated as “Compound (5)”) which does not engagein the reaction. Accordingly, Compound (3) in the reaction becomesinsufficient and then the reaction time comes to be unstabilized. In thepresent invention, an excess amount of Compound (3) is used, thusCompound (3) does not run short and the reaction can be steadily carriedout (i.e. shortening the reaction time and enhancing the transformationrate) even though Compound (5) is produced. In addition, potassiumcarbonate which is used as a base for reviving Compound (3) fromCompound (5) can be deleted or reduced in the present invention, thusthe present invention can hold down the producing of by-product (R) andmake it possible to prepare quaternary ammonium salt (4) in stably highquality, particularly with an industrial advantage. Particularly, in anindustrial scale process, it is possible to shorten the reaction timeand enhance the transformation rate.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention is further illustrated. The numberadditionally-described in each “substituent” such as “C₁₋₆” means thenumber of carbons contained therein. For example, “C₁₋₆ alkyl” means analkyl group having 1 to 6 carbon atoms.

The number of substituents defined in an “optionally substituted” or“substituted” group is not limited as long as the substitution ispossible, and the number may be one or more. Each substituent usedherein may be applied as a part of other substituent or a substituent ofother substituent, unless otherwise indicated.

The term “halogen atom” used herein includes, for example, fluorineatom, chlorine atom, bromine atom and iodine atom, and preferablyfluorine atom or chlorine atom.

The term “C₁₋₆ alkyl group” used herein means a straight or branchedchain saturated hydrocarbon group having 1-6 carbon atoms, and thepreferable one is “C₁₋₄ alkyl group”. The “C₁₋₆ alkyl group” includes,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl,hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, and 2-ethylbutyl.

The term “C₃₋₇ cycloalkyl group” used herein means a cyclic saturatedhydrocarbon group having 3-7 carbon atoms, and the preferable one is“C₃₋₆ cycloalkyl group”. The “C₃₋₇ cycloalkyl group” includes, forexample, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “C₆₋₁₀ aryl group” used herein means an aromatic hydrocarbongroup having 6-10 carbon atoms, and the preferable one is “C₆ arylgroup” (i.e. phenyl). The “C₆₋₁₀ aryl group” includes, for example,phenyl, 1-naphthyl and 2-naphthyl.

The term “C₁₋₆ alkoxy group” used herein means a C₁₋₆ alkyloxy group,wherein the C₁₋₆ alkyl moiety is defined as the above-mentioned “C₁₋₆alkyl”, and the preferable one is “C₁₋₄ alkoxy group”. The “C₁₋₆ alkoxygroup” includes, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term “C₃₋₇ cycloalkoxy group” used herein means a C₃₋₇ cycloalkyloxygroup, wherein the C₃₋₇ cycloalkyl moiety is defined as theabove-mentioned “C₃₋₇ cycloalkyl”. The “C₃₋₇ cycloalkoxy group”includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,and cyclohexyloxy.

The “C₆₋₁₀ aryl” moiety in the term “C₆₋₁₀ aryloxy group” used herein isdefined as the above-mentioned “C₆₋₁₀ aryl”, and the preferable “C₆₋₁₀aryloxy group” is “C₆ aryloxy” (i.e. phenyloxy). The “C₆₋₁₀ aryloxygroup” includes, for example, phenoxy, 1-naphthyloxy and 2-naphthyloxy.

The “C₁₋₆ alkyl” moiety in the term “C₁₋₆ alkylthio group” used hereinis defined as the above-mentioned “C₁₋₆ alkyl”, and the preferable “C₁₋₆alkylthio group” is “C₁₋₄ alkylthio group”. The “C₁₋₆ alkylthio group”includes, for example, methylthio, and ethylthio.

The “C₃₋₇ cycloalkyl” moiety in the term “C₃₋₇ cycloalkylthio group”used herein is defined as the above-mentioned “C₃₋₆ cycloalkyl”. The“C₃₋₇ cycloalkylthio group” includes, for example, cyclopropylthio,cyclobutylthio, cyclopentylthio, and cyclohexylthio.

The “C₆₋₁₀ aryl” moiety in the term “C₆₋₁₀ arylthio group” used hereinis defined as the above-mentioned “C₆₋₁₀ aryl”. The “C₆₋₁₀ arylthiogroup” includes, for example, phenylthio, 1-naphthylthio and2-naphthylthio.

The “C₁₋₆ alkyl” moiety in the term “C₁₋₆ alkylsulfonyloxy group” usedherein is defined as the above-mentioned “C₁₋₆ alkyl”, and thepreferable “C₁₋₆ alkylsulfonyloxy group” is “C₁₋₄ alkylsulfonyloxygroup”.

The “C₁₋₆ alkylsulfonyloxy group” includes, for example,methylsulfonyloxy, and ethylsulfonyloxy.

The “C₆₋₁₀ aryl” moiety in the term “C₆₋₁₀ arylsulfonyloxy group” usedherein is defined as the above-mentioned “C₆₋₁₀ aryl”. The “C₆₋₁₀arylsulfonyloxy group” includes, for example, phenylsulfonyloxy,1-naphthylsulfonyloxy and 2-naphthylsulfonyloxy.

The “heteroaryl group” used herein includes, for example, a 5- to10-membered monocyclic or multi-cyclic aromatic group having one or moreheteroatoms (e.g. 1 to 4 heteroatoms) independently-selected fromnitrogen, sulfur, and oxygen atom. The “multi-cyclic heteroaryl group”preferably includes a bicyclic or tricyclic one, and more preferably abicyclic one. The “multi-cyclic heteroaryl group” also includes a fusedcyclic group of the above-mentioned monocyclic heteroaryl group with theabove-mentioned aromatic ring group (e.g. benzene) or non-aromatic ringgroup (e.g. cyclohexyl). The “heteroaryl group” includes, for example,the following groups.

The bond used herein which is connected to the middle of a bond in aring compound is meant to be attached to any possible position of thering. For example, the heteroaryl group of the following formula:

means 2-furyl group, or 3-furyl group.

In case that “heteroaryl group” is a multiple-cyclic group, for example,in case of the following group:

it means 2-benzofuryl group, or 3-benzofuryl group, and additionally, itmay mean 4-, 5-, 6- or 7-benzofuryl group. However, in case that amultiple-cyclic heteroaryl group which is composed by fusing an aromaticring and non-aromatic ring (e.g. piperidine), only the positions in thearomatic ring have the bond. For example, the “multiple-cyclicheteroaryl group” such as the following group:

means to be bound on 2-, 3-, or 4-position.

The “heteroaryl” moiety in the term “heteroaryloxy group” used herein isdefined as the above-mentioned “heteroaryl group”. The “heteroaryloxygroup” includes, for example, pyridyloxy.

The “heteroaryl” moiety in the term “heteroarylthio group” used hereinis defined as the above-mentioned “heteroaryl group”. The“heteroarylthio group” includes, for example, pyridylthio.

The “C₅₋₇ cycloalkenyl group” used herein includes a cycloalkenyl grouphaving 5-7 carbon atoms such as cyclopentenyl group, cyclohexenyl group,and cycloheptenyl group.

The “C₅₋₇ cycloalkenyloxy group” used herein includes a group composedof the above-mentioned cycloalkenyl group and oxygen atom, such ascyclopentenyloxy group.

The “C₅₋₇ cycloalkenylthio group” used herein includes theabove-mentioned cycloalkenyloxy group wherein the oxygen atom isreplaced by sulfur atom, such as cyclohexylthio group.

The “C₁₋₄ alkylene” used herein has 1-4 carbon atoms and includes, forexample, methylene, ethylene, and trimethylene.

The “C₁₋₃ alkylene” used herein has 1-3 carbon atoms and includes, forexample, methylene, ethylene, and trimethylene.

The “hydrocarbon ring” used herein is a cyclic alkane having 3-7 carbonatoms such as C₃₋₇ cycloalkane, or a cyclic alkene having 5-7 carbonatoms such as C₅₋₇ cycloalkene. The cyclic alkane having 3-7 carbonatoms includes, for example, cyclopropane, cyclobutane, cyclopentane,cyclohexane, cycloheptane. The cyclic alkene having 5-7 carbon atomsincludes, for example, cyclopentene, cyclohexene, and cycloheptene.

The “aromatic hydrocarbon ring” used herein means a ring containing theabove-mentioned “C₆₋₁₀ aryl” moiety.

The “counteranion” includes, for example, halogen ion (e.g. chlorineion), sulfate ion, hydrogensulfate ion, phosphate ion, hydrogenphosphateion, dihydrogenphosphate ion, C₁₋₆ alkylsulfonate ion (e.g.methanesulfonate ion), C₆₋₁₀ arylsulfonate ion (e.g. p-toluenesulfonateion), and hydroxide ion.

The “by-product which is produced by the reaction with potassiumcarbonate wherein the by-product has a carbonate part therein”(by-product (R)) is all-inclusive term of by-products having at leastone carbonate parts therein. In the present specification, theseby-products are expressed as “by-product (R)”, and the producing ratesof by-product (R) in the examples mentioned below are used as anevaluation of the present invention.

Compound (1) includes, for example, 1,4-dibromobutane,1,4-dichlorobutane, 1,4-diiodobutane, 1,4-dimethanesulfonyloxybutane,1,4-di(p-toluenesulfonyloxy)-butane, 2-hydroxy-1,3-dibromopropane,2-hydroxy-1,3-dichloropropane,2-hydroxy-1,3-dimethanesulfonyloxypropane,1,2-bis(bromomethyl)cyclohexane,1,2-bis(methanesulfonyl-oxymethyl)cyclohexane,1,2-bis(bromomethyl)cyclopentane,1,2-bis(methanesulfonyloxymethyl)cyclopentane,2,3-bis(bromomethyl)-bicyclo[2.2.1]heptane,2,3-bis(methane-sulfonyloxymethyl)-bicyclo[2.2.1]heptane,4,5-bis(bromo-methyl)-1-cyclohexene,4,5-bis(methanesulfonyloxymethyl)-1-cyclohexene, and2,3-bis(bromomethyl)-7-oxabicyclo[2.2.1]-hept-5-ene.

As Compound (1) used herein, a commercially available compound may beused. In case that Compound (1) has a chiral carbon(s), i.e. it has anoptical isomer, the compound herein may be a single optical isomer, aracemic compound thereof, or a mixture of optical isomers in a certainratio.

A preferable example of Compound (1) includes a compound of thefollowing formula:

wherein Ms means methanesulfonyl group.

In Compound (3), C₁₋₆ alkyl group, C₃₋₇ cycloalkyl group, C₅₋₇cycloalkenyl group, C₆₋₁₀ aryl group, and 5- to 10-membered monocyclicor bicyclic heteroaryl group in “R³”; and C₁₋₆ alkyl group, C₁₋₆ alkoxygroup, C₁₋₆ alkylthio group, C₃₋₇ cycloalkyl group, cycloalkyloxy group,C₃₋₇ cycloalkylthio group, C₅₋₇ cycloalkenyl group, C₅₋₇ cycloalkenyloxygroup, C₅₋₇ cycloalkenylthio group, C₆₋₁₀ aryl group, C₆₋₁₀ aryloxygroup, C₆₋₁₀ arylthio group, 5- to 10-membered monocyclic or bicyclicheteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxygroup, and 5- to 10-membered monocyclic or bicyclic heteroarylthio groupin “R⁴” may be further optionally substituted with the same or differentone to three substituents selected from the group consisting of C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio and halogen atom.

Compound (3) includes, for example, 4-phenylpiperazine,4-(2methoxyphenyl)piperazine, 4-cyclohexylpiperazine,4-(2-pyridinyl)piperazine, 4-(2-pyrimidinyl)piperazine,4-(2-quinolyl)piperazine, 4-(4-quinolyl)piperazine,4-(1,2-benzisothiazol-3-yl)piperazine, 4-(4-fluorophenyl)piperidine,4-[(4-fluorophenyl)thio]-piperidine, 4-(3-chlorophenyl)piperazine,4-(1,2-benzisoxazol-3-yl)piperidine, 4-(5-benzofuranyl)piperazine,4-(1-naphthyl)piperazine, 4-[bis(4-fluorophenyl)methylene]-piperidine,4-(3-isoquinolyl)piperazine, 4-(8-quinolyl)-piperazine,4-(7-benzofuranyl)piperazine, and4-(5-fluoro-1,2-benzisoxazol-3-yl)piperidine. The preferable example is4-(1,2-benzisothiazol-3-yl)piperazine.

Compound (3) can be prepared according to, for example, JP 63(1988)-83085 A, J. Med. Chem., 28761 (1985), and J. Med. Chem., 32, 1024(1989). And, Compound (3) may include an addition acid salt thereof (3)such as a hydrochloride and a sulfate thereof.

In the reaction between Compound (1) and Compound (3) in the presentinvention, Compound (3) is used in an excess amount for Compound (1).The amount of Compound (3) used herein is preferably 1.5 mole to 15 moleper one mole of Compound (1), more preferably, 1.8 mole to 5 mole perone mole of Compound (1), typically 2 mole per one mole of Compound (1).The upper limit amount of Compound (3) used herein is not limited, but,in case that the amount is too much, the by-product of formula (6):

wherein Y and Z are as defined in the above Term 1 (hereinafter,abbreviated as “by-product (6)”) tends to increase. Accordingly, theamount of Compound (3) used is practically not more that 5 mole per onemole of Compound (1). The reaction can proceed without potassiumcarbonate when 2 mole of Compound (3) is used per one mole of Compound(1), hence quaternary ammonium salt (4) of formula (4):

wherein X, Y and Z are as defined in the above Term 1, can be preparedwith a steady quality while the production of by-product (R) can be helddown.

In the present invention, it is possible to react Compound (1) andCompound (3) in two steps (in two-step addition). Namely, it ispreferable to react each partial amount of Compound (1) and Compound (3)firstly, and then add the rests of Compound (1) and Compound (3) to thereaction mixture to complete the reaction. In detail, it is morepreferable to react 0.1 to 1.0 time of Compound (1) per the total amountof Compound (1) and 0.1 to 1.0 time of Compound (3) per the total amountof Compound (1) (step i), then add the rest of Compound (1) and 1.8 to5.0 times of Compound (3) per the total amount of Compound (1) to thereaction mixture to complete the reaction (step ii).

In the reaction between Compound (1) and Compound (3), a solid inorganicbase (salt) may be coexistent. The solid inorganic base (salt) includes,for example, an alkali metal carbonate such as potassium carbonate, andsodium carbonate; an alkali earth metal salt such as calcium carbonate,and magnesium carbonate; and an alkali metal bicarbonate such as sodiumbicarbonate, and potassium bicarbonate; preferably an alkali metalcarbonate, in particular, potassium carbonate. Such solid inorganic basemay be used alone or as a mixture of two or more kinds of bases. And,such solid inorganic base may be an anhydrous form or a hydrate thereof.

The upper limit amount of the solid inorganic base used herein is notlimited, but, in case that the amount is too much, by-productsincreases. Accordingly, the general amount of the solid inorganic baseused is preferably 0.1 to 0.3 mole per one mole of the total amount ofCompound (1). And, in case of using an acid addition salt of Compound(3), it is preferable to add an additional appropriate amount of a baseto neutralize the acid addition salt.

If Compound (5) of formula (5):

wherein X⁻ is an counteranion, and Z is as defined in the above Term 1,precipitates as an oil, not as a crystal in the reaction, i.e. theaspect of the reaction solution is not good, the aspect can be improvedby add a crystal seed of Compound (5) thereto to promote thecrystallization of Compound (5). Or, it is also possible to improve itby preparing a small amount of the crystal seed of Compound (5) in thepre-reaction, and then reacting Compound (1) and Compound (3). However,Compound (5) cannot sometimes be crystallized due to its property.

The solvent used herein includes, for example, an alcohol solvent suchas methanol, and ethanol; an aprotic polar solvent such as acetonitrile,and N,N-dimethylformamide; aromatic carbon ring solvent such as toluene,and xylene; which can be used alone or in a mixture of two or more kindsof the solvents and the amount of the solvent used is not limited.

The reaction temperature is generally 60 to 180° C., preferably 90 to150° C.

After the reaction is completed, for example, the reaction mixture or apart of the reaction mixture can be concentrated and then filtrated togive a mixture of the quaternary ammonium salt (4) and Compound (5). Inaddition, the reaction mixture containing quaternary ammonium salt (4)and Compound (5) may be used in the reaction mentioned below withouttaking out quaternary ammonium salt (4) from the mixture.

Quaternary ammonium salt (4) thus prepared includes, for example,chloride, bromide, iodide, hydroxide, sulfate, hydrogensulfate,phosphate, hydrogenphosphate, dihydrogen-phosphate, methanesulfonate,and p-toluenesulfonate of

-   7-cyclohexyl-2-hydroxy-7-aza-4-azoniaspiro[3.5]-nonane,-   8-phenyl-8-aza-5-azoniaspiro[4.5]decane,-   8-(2-methoxyphenyl)-8-aza-5-azoniaspiro[4.5]decane,-   8-(2-pyridinyl)-8-aza-5-azoniaspiro[4.5]decane,-   8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane,-   8-(2-quinolyl)-8-aza-5-azoniaspiro[4.5]decane,-   8-(4-quinolyl)-8-aza-5-azoniaspiro[4.5]decane,-   8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro-[4.5]decane,-   4′-(1,2-benzisothiazol-3-yl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-[(4-fluorophenyl)thio]octahydro-spiro[2H-isoindole-2,1′-piperidinium],-   4′-(2-pyrimidinyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(4-fluorophenoxy)octahydro-spiro[2H-isoindole-2,1′-piperidinium],-   4′-(1,2-benzisoxazol-3-yl)octahydro-spiro[2H-isoindole-2,1′-piperidinium],-   4′-(6-fluoro-1,2-benzisoxazol-3-yl)-octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(2-pyridinyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(3-chlorophenyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(5-benzofuranyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(1-naphthyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-[bis(4-fluorophenyl)methylene]octahydro-spiro[2H-isoindole-2,1′-piperidinium],-   4′-(2-methoxyphenyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(3-isoquinolyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(8-quinolyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(1,2-benzisothiazol-3-yl)tetrahydro-spiro-[cyclopenta[c]pyrrole-2(1H),    1′-piperazinium],-   4′-(1,2-benzisothiazol-3-yl)octahydro-spiro[4,7-methano-2H-isoindole-2,1′-piperazinium],-   4′-(1,2-benzisothiazol-3-yl)-1,3,3a,4,7,7a-hexahydro-spiro[2H-isoindole-2,1′-piperazinium],-   4′-(1,2-benzisothiazol-3-yl)-1,3,3a,4,7,7a-hexahydro-spiro[4,7-epoxy-2H-isoindole-2,1′-piperazinium],    or-   4′-(7-benzofuranyl)octahydro-spiro[2H-isoindole-2,1′-piperazinium].

By reacting the resulting quaternary ammonium salt (4) and a compound offormula (7):

wherein the symbols are as defined in the above Term 17 (hereinafter,abbreviated as “Compound (7)”) in the presence of a solid inorganicbase, an imide compound of formula (8):

wherein the symbols are as defined in the above Term 17 (hereinafter,abbreviated as “imide compound (8)”) can be prepared.

Compound (7) includes a compound of the following formula (7a):

wherein -L- is a single or double bond, E is C₁₋₃ alkylene optionallysubstituted with C₁₋₄ alkyl or oxygen atom, R^(5e) is hydrogen atom orC₁₋₄ alkyl group, and B is as defined in the above formula (7).

Compound (7) includes, for example, succinimide, 2,6-piperidine-dione,4,4-dimethyl-2,6-piperidine-dione, 8-azaspiro[4.5]decane-7,9-dione,perhydroazepin-2,7-dione, maleimide, phthalimide, tetrahydrophthalimide,cis-1,2-cyclohexane-dicarboximide, trans-1,2-cyclohexane-dicarboximide,cis-1,2-cyclohex-4-ene-dicarboximide,trans-1,2-cyclohex-4-ene-dicarboximide,cis-4-methyl-1,2-cyclo-hexane-dicarboximide,trans-4-methyl-1,2-cyclohexane-dicarboximide,cis-1,2-dimethyl-1,2-cyclohexane-dicarboximide,trans-1,2-dimethyl-1,2-cyclohexane-dicarboximide,cis-4,5-dimethyl-1,2-cyclohexane-dicarboximide,trans-4,5-dimethyl-1,2-cyclohexane-dicarboximide,cis-3,6-dimethyl-1,2-cyclohexane-dicarboximide,trans-3,6-dimethyl-1,2-cyclohexane-dicarboximide,bicyclo[2.2.1]heptane-2,3-di-exo-carboximide,bicyclo[2.2.1]heptane-2,3-di-endo-carboximide,bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboximide,bicyclo-[2.2.1]hept-5-ene-2,3-di-endo-carboximide,bicyclo[2.2.2]-octane-2,3-di-exo-carboximide,bicyclo[2.2.2]octane-2,3-di-endo-carboximide,bicyclo[2.2.2]oct-5-ene-2,3-di-exo-carboximide,bicyclo[2.2.2]oct-5-ene-2,3-di-endo-carboximide,bicyclo[2.2.2]oct-7-ene-2,3-di-exo-carboximide,bicyclo[2.2.2]oct-7-ene-2,3-di-endo-carboximide,hexahydro-4,7-methano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide,3,6-epoxy-1,2-cyclohexane-dicarboximide, andspiro[bicyclo[2.2.2]octane-2,3′-pyrrolidine]-2′,5′-dione.

A preferable example of Compound (7) includes a compound of thefollowing (7b):

Compound (7b) can include its optical isomers, thus the compound usedherein may be one of the optical isomers or a mixture of the opticalisomers. A preferable example of Compound (7) includes a compound of thefollowing formula:

or a salt thereof.

Compound (7) can be prepared, for example, by reacting a correspondingcarboxylic anhydride compound and ammonia (for example,JP-1(1989)-199967 A).

The solid inorganic base (salt) includes, for example, an alkali metalcarbonate such as potassium carbonate, and sodium carbonate; an alkaliearth metal salt such as calcium carbonate, and magnesium carbonate; andan alkali metal bicarbonate such as sodium bicarbonate, and potassiumbicarbonate; preferably an alkali metal carbonate, in particular,potassium carbonate. Such solid inorganic base may be used alone or as amixture of two or more kinds of bases. And, such solid inorganic basesmay be an anhydrous form or a hydrate thereof.

The amount of the solid inorganic base used herein is generally 0.7 moleor more, preferably 0.9 mole or more per one mole of the total amount ofCompound (1) or quaternary ammonium salt (4). The upper limit amount ofthe solid inorganic base used herein is not limited, but, in case thatthe amount is too much, the process cost increases. Accordingly, thepractical amount of the solid inorganic base is 3 mole or less,preferably 2.7 mole or less per one mole of the total amount of Compound(1) or quaternary ammonium salt (4).

The amount of Compound (7) used herein is generally 0.7 mole or more perone mole of the total amount of Compound (1) or quaternary ammonium salt(4). The upper limit amount of Compound (7) used herein is not limited,but, in case that the amount is too much, the process cost increases.Accordingly, the practical amount of Compound (7) is 2.5 mole or lessper one mole of the total amount of Compound (1) or quaternary ammoniumsalt (4).

The reaction of the present invention is generally carried out in thepresence of a solvent. The solvent used herein includes, for example,aromatic hydrocarbons such as toluene, xylene, mesitylene,chlorobenzene, and dichlorobenzene. The amount of such solvent usedherein is generally 3 parts by weight or more, preferably 5 parts byweight or more per one part by weight of the total amount of Compound(1) or quaternary ammonium salt (4). The upper limit amount of thesolvent used herein is not limited, but, in case that the amount is toomuch, the volumetric efficiency is turned down. Accordingly, thepractical amount of the solvent is 20 parts by weight or less per onepart by weight of the total amount of Compound (1) or quaternaryammonium salt (4).

The reaction of the present invention is preferably carried out in thecoexistence of water, i.e. in the presence of generally 0.05 to 3 mole,preferably 0.1 to 1.5 mole of water per one mole of the total amount ofCompound (1) or quaternary ammonium salt (4). When using a hydrate ofsolid inorganic base, the amount of water used herein may be decidedconsidering the water of the hydrate. The water may initially exist inthe reaction medium or an appropriate amount of water may be addedthereto in mid-course. Or, the water may be added to Compound (7) and/orquaternary ammonium salt (4) beforehand.

In addition, the reaction of the present invention may be carried out inthe coexistence of a phase-transfer catalyst such as tetra-n-butylammonium hydrogen sulfate, tetra-n-butyl ammonium bromide, and benzyltriethyl ammonium chloride. The amount of the phase-transfer catalystused herein is generally 0.01 to 0.5 mole per one mole of the totalamount of Compound (1) or quaternary ammonium salt (4).

The reaction temperature is generally 80 to 180° C., preferably 95 to150° C.

The reaction of quaternary ammonium salt (4) and Compound (7) isgenerally carried out by contacting and mixing quaternary ammonium salt(4), Compound (7) and a solid inorganic base, and the addition order ofthe substances is not limited. The solid inorganic base may be addedthereto in separated amounts or in a lump, but it is preferable in alump.

The reaction mixture containing imide compound (8) is obtained after thereaction, and the mixture can be treated by adding water thereto, mixingit, standing still in a whole, separating it with a separating funnel,optionally treating the organic layer with active carbon, andconcentrating the organic layer to give imide compound (8).Alternatively, imide compound (8) can be obtained as a crystal bycooling the above-mentioned organic layer or the partially-concentratedorganic layer, or adding another solvent which is comparativelyinsoluble for imide compound (8) to the organic layer. The solvent whichis comparatively insoluble for imide compound (8) includes, for example,an aliphatic hydrocarbon solvent such as pentane, hexane, and heptane,and an alcohol solvent such as methanol, ethanol, and isopropanol.

In addition, imide compound (8) can be also obtained from the reactionmixture containing imide compound (8) by removing out insolubleprecipitates with a filter and concentrating the filtrate. Further,imide compound (8) can be obtained as a crystal by cooling the reactionmixture or the partially-concentrated reaction mixture, or addinganother solvent which is comparatively insoluble for imide compound (8)to the organic layer.

The obtained imide compound (8) may be further purified by aconventional purification such as recrystallization and chromatography.In addition, imide compound (8) can be obtained as an inorganic acidaddition salt such as hydrochloride, sulfate, hydrobromide, andphosphate; or an organic acid addition salt such as acetate, oxalate,citrate, malate, tartrate, maleate, and fumarate.

The imide compound (8) prepared herein includes, for example,

-   2-[4-(4-phenyl-1-piperazinyl)butyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[4-(4-phenyl-1-piperazinyl)butyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[([4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione    (2-[2-[(4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione),-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1,2-benzisothiazole-3(2H)-one-1,1-dioxide,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione,-   8-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-8-azaspiro[4,5]decane-7,9-dione,-   1-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-4,4-dimethyl-2,6-piperidine-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione,-   1′-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-spiro[bicyclo[2.2.2]octane-2,3′-pyrrolidine]-2′,5′-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-3a,7a-dimethyl-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-3a,4,7,7a-tetrahydro-4,7-ethano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-ethano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclohexyl]methyl]-4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-[(4-fluorophenyl)thio]-1-piperidyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-[(4-fluorophenyl)thio]-1-piperidyl]-methyl]cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(4-fluorophenoxy)-1-piperidyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisoxazol-3-yl)-1-piperidyl]-methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisoxazol-3-yl)-1-piperidyl]-methyl]cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidyl]methyl]cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-pyridinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-pyrimidinyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(3-chlorophenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(3-chlorophenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(5-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(5-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1-naphthyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1-naphthyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-[bis(4-fluorophenyl)methylene]-1-piperidyl]methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-[bis(4-fluorophenyl)methylene]-1-piperidyl]methyl]cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(3-isoquinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(3-isoquinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(8-quinolyl)-1-piperazinyl]methyl]cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(8-quinolyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclopentyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]cyclopentyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]bicyclo[2.2.1]hept-2-yl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]bicyclo[2.2.1]hept-2-yl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,-   2-[[2-[[4-(7-benzofuranyl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-yl]methyl]-hexahydro-4,7-methano-1H-isoindole-1,3(2M-dione,-   2-[[3-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-7-oxabicyclo[2.2.1]hept-5-ene-2-yl]methyl]-hexahydro-1H-isoindole-1,3(2H)-dione,-   2-[[6-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-3-cyclohexen-1-yl]methyl]hexahydro-4,7-methano-1H-isoindole-1,3(2H)-dione,    and-   2-[[6-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-methyl]-3-cyclohexen-1-yl]methyl]hexahydro-1H-isoindole-1,3(2H)-dione.

In case that the optically active compound (7) and/or the opticallyactive quaternary ammonium salt (4) are used in the reaction, theoptically active corresponding imide compound (8) can be obtained.

In addition, the present invention includes the following process:

wherein the symbols described in the scheme are as defined in Terms 1and 17 mentioned above.

EXAMPLE

Hereinafter, the present invention is illustrated in more detail by thefollowing Example and Comparative Example, but it should not beconstrued to be limited thereto. The analyses in the examples were doneby high-performance liquid chromatography (LC) or gas chromatography.

Example 1

A mixed solution of 4-(1,2-benzisothiazol-3-yl)piperazine [Compound (A)](20.0 g, 91.2 mmol),(1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane [Compound (B)](13.7 g, 45.6 mmol), and toluene (140 g) was stirred under reflux for 3hours to give a reaction mixture containing4′-(1,2-benzisothiazol-3-yl)-(3aR,7aR)-octahydro-spiro[2H-isoindole-2,1′-piperazinium]methanesulfonate[Compound (C)]. And, the production rate of by-product (R) was 0.025%(which was calculated with the following formula (a)).

$\begin{matrix}{{{Production}\mspace{14mu}{rate}\mspace{14mu}{of}\mspace{14mu}{by}\text{-}{product}\mspace{14mu}{derived}\mspace{14mu}{from}\mspace{14mu}{carbonate}} = {\frac{\begin{matrix}{{Total}\mspace{14mu} L\; C\mspace{14mu}{area}\mspace{14mu}{of}} \\{{by}\text{-}{product}\mspace{14mu}{derived}\mspace{14mu}{from}\mspace{14mu}{carbonate}}\end{matrix}}{\begin{matrix}{{Total}\mspace{14mu} L\; C\mspace{14mu}{area}\mspace{14mu}{of}} \\{{detected}\mspace{14mu}{peaks}\mspace{14mu}{except}\mspace{14mu}{solvent}}\end{matrix}} \times 100}} & (a)\end{matrix}$

Example 2

To the reaction mixture containing Compound (C) which was obtained inthe above Example 1 were added tetra-n-butyl ammonium hydrogen sulfate(0.62 g, 1.83 mmol),(3aR,4S,7R,7aS)-hexahydro-4,7-methano-2H-isoindole-1,3-dione [Compound(D)] (11.3 g, 68.4 mmol), potassium carbonate (7.6 g, 55.0 mmol) andwater (0.4 g), and the resulting mixture was reacted under reflux for 3hours. Then, the reaction mixture was cooled to room temperature, andwater (200 g) was added to the mixture. The mixture was separated with aseparating funnel, and the toluene layer was washed with 2.3% (W/W)brine (175 g). Further, active carbon (0.9 g) was added to the toluenesolution, and the mixture was stirred for 1 hour. The active carbon wasremoved by filtration to give a toluene solution containing(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]cyclohexylmethyl}-hexahydro-4,7-methano-2H-isoindole-1,3-dione(2-[[(1R,2R)-2-[[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]methyl]-cyclohexyl]methyl]hexahydro-(3aS,4R,7S,7aR)-4,7-methano-1H-isoindole-1,3(2H)-dione)[Compound (E)] (266.5 g). The yield of Compound E was 94.3%. The yieldof Compound (E) was calculated based on the analytical result that thecontent of the compound in the toluene solution was 7.9% (w/w) (whichwas calculated by LC absolute calibration curve method). And, theproduction rate of by-product (R) was 0.12% (which was calculated withthe above formula (a)).

Example 3

To a mixture of Compound (A) (6.0 g, 27.4 mmol), Compound (B) (9.9 g,33.0 mmol) and toluene (84 g) was added potassium carbonate (2.3 g, 16.6mmol), and the mixture was reflux-dehydrated for 4 hours. After coolingthe reaction mixture to 70° C. or lower, toluene (196 g), Compound (A)(34.0 g, 155.0 mmol) and Compound (B) (17.5 g, 58.3 mmol) were added tothe reaction mixture, and then the reaction mixture wasreflux-dehydrated again for 9 hours to give the reaction mixturecontaining Compound (C). The remained amount of Compound (B) in thesupernatant toluene was 2.4% (which was calculated by GC absolutecalibration curve method) (transformation rate: 97.6%). And, theproduction rate of by-product (R) was 0.31% which was analyzed by LCanalysis and calculated with the above formula (a).

Example 4

To the reaction mixture containing Compound (C) which was obtained inthe above Example 3 were added toluene (44.0 g), Compound (D) (16.6 g,100.5 mmol) and potassium carbonate (25.2 g, 182.3 mmol), and then thetoluene (44 g) was removed by heating. Then, the reaction mixture wascooled to 70° C. or lower, and water (0.8 g) was added to the mixture.The mixture was refluxed for 3 hours and it was checked that theproduction rate of by-product (6) was 0.10% (which was calculated withthe following formula (b)).

$\begin{matrix}{{{Production}\mspace{14mu}{rate}\mspace{14mu}{of}\mspace{14mu}{by}\text{-}{product}\mspace{14mu}(6)(\%)} = \frac{{LC}\mspace{14mu}{area}\mspace{14mu}{of}\mspace{14mu}{by}\text{-}{product}\mspace{14mu}(6)}{\begin{matrix}{{LC}\mspace{14mu}{area}\mspace{14mu}{of}} \\{{by}\text{-}{product}\mspace{14mu}(6)}\end{matrix} + \begin{matrix}{( {{3\;{aR}},{4\; S},{7\; R},{7\;{aS}}} ) - 2 -} \\\begin{Bmatrix}{( {{1\; R},{2\; R}} ) - 2 -} \\{\begin{bmatrix}{4 - \begin{pmatrix}{1,{2 - {benzisothiazol} -}} \\{3 - {+ {yl}}}\end{pmatrix}} \\{{piperazin} - 1 - {ylmethyl}}\end{bmatrix} -} \\{cyclohexylmethyl}\end{Bmatrix} \\{{{hexahydro} - 4},{7 - {methano} - {2\; H} -}} \\{{{isoindole} - 1},{3 - {dione}}}\end{matrix}}} & (b)\end{matrix}$

The reaction mixture was cooled, and water (400.0 g) was added to themixture. The mixture was separated with a separating funnel, and thetoluene layer was washed with 0.8% hydrochloric acid (400 g), and then2.3, % (w/w) brine (350 g). Further, active carbon (1.8 g) was added tothe toluene solution, and the mixture was stirred for 1 hour. The activecarbon was removed by filtration and washed with toluene to give atoluene solution containing Compound (E) (385.1 g). The yield ofCompound E was 93.4%. The yield of Compound (E) was calculated based onthe analytical result that the content of the compound in the toluenesolution was 10.9% (w/w) (which was calculated by LC absolutecalibration curve method). And, the production rate of by-product (R)was 1.21% (which was calculated with the above formula (a)).

Example 5

To a mixture of Compound (A) (6.0 g, 27.4 mmol), Compound (B) (9.9 g,33.0 mmol) and toluene (84 g) was added potassium carbonate (2.3 g, 16.6mmol), and the resulting mixture was reflux-dehydrated for 4 hours.After cooling the reaction mixture to 70° C. or lower, toluene (196 g),Compound (A) (94.0 g, 428.6 mmol) and Compound (B) (17.5 g, 58.3 mmol)were added to the reaction mixture, and then the reaction mixture wasreflux-dehydrated again for 4 hours to give the reaction mixturecontaining Compound (C). The remained amount of Compound (B) in thesupernatant toluene was less than the detection limit of GC(transformation rate: 100%). And, the production rate of by-product (R)was 0.09% which was analyzed by LC analysis and calculated with theabove formula (a).

Example 6

To the reaction mixture containing Compound (C) which was obtained inthe above Example 5 were added toluene (44.0 g), Compound (D) (16.6 g,100.5 mmol) and potassium carbonate (25.2 g, 182.3 mmol), and then thetoluene (44 g) was removed by heating. Then, the reaction mixture wascooled to 70° C. or lower, and water (0.8 g) was added to the mixture.The mixture was refluxed for 2 hours and it was checked that theproduction rate of by-product (6) was 0.10% (which was calculated withthe above formula (b)). The reaction mixture was cooled, and water(400.0 g) was added to the mixture. The mixture was separated with aseparating funnel, and the toluene layer was washed with 1.6%hydrochloric acid (800 g), and then 2.3% (w/w) brine (350 g). Further,active carbon (1.8 g) was added to the toluene solution, and the mixturewas stirred for 1 hour. The active carbon was removed by filtration andwashed with toluene to give a toluene solution containing Compound (E)(385.1 g). The yield of Compound (E) was 91.5%. The yield of Compound(E) was calculated based on the analytical result that the content ofthe compound in the toluene solution was 10.4% (w/w) (which wascalculated by LC absolute calibration curve method). And, the productionrate of by-product (R) was 1.85% (which was calculated with the aboveformula (a)).

Example 7

To a mixture of Compound (A) (6.0 g, 27.4 mmol), Compound (B) (9.9 g,33.0 mmol) and toluene (97 g) was added potassium carbonate (2.3 g, 16.6mmol), the toluene (13.4 g) was removed by heating, and then the mixturewas reflux-dehydrated for 4 hours. After cooling the reaction mixture to70° C. or lower, toluene (227 g), Compound (A) (30.0 g, 136.8 mmol) andCompound (B) (17.5 g, 58.3 mmol) were added to the reaction mixture, thetoluene (30.6 g) was removed, and then the reaction mixture wasreflux-dehydrated again for 20 hours to give the reaction mixturecontaining Compound (C). The remained amount of Compound (B) in thesupernatant toluene was 1.4% (transformation rate: 98.6%). And, theproduction rate of by-product (R) was 1.28% which was analyzed by LCanalysis and calculated with the above formula (a).

Example 8

To the reaction mixture containing Compound (C) which was obtained inthe above Example 7 were added toluene (44.0 g), Compound (D) (16.6 g,100.5 mmol) and potassium carbonate (22.7 g, 164.2 mmol), and then thetoluene (44 g) was removed by heating. Then, the reaction mixture wascooled to 70° C. or lower, and water (0.8 g) was added to the mixture.The mixture was refluxed for 4.5 hours. The reaction mixture was cooled,and water (400.0 g) was added to the mixture. The mixture was separatedwith a separating funnel, and the toluene layer was washed with 3.6%hydrochloric acid (313 g), and then 2.3% (w/w) brine (350 g). Further,active carbon (1.8 g) was added to the toluene solution, and the mixturewas stirred for 1 hour. The active carbon was removed by filtration andwashed with toluene to give a toluene solution containing Compound (E)(413.3 g). The yield of Compound (E) was 85.6%. The yield of Compound(E) was calculated based on the analytical result that the content ofthe compound in the toluene solution was 9.3% (w/w) (which wascalculated by LC absolute calibration curve method). And, the productionrate of by-product (R) was 1.44% (which was calculated with the aboveformula (a)).

Comparative Example 1

To a mixture of Compound (A) (140.1 kg, 638.8 mol), Compound (B) (230.3kg, 766.7 mol) and toluene (2272 kg) was added potassium carbonate (53.0kg, 383.5 mol), the toluene (312 kg) was removed by heating, and thenthe mixture was reflux-dehydrated for 5 hours. Then, the reactionmixture was cooled to 70° C. or lower, and potassium carbonate (26.5 kg,191.7 mol) and tetra-n-butyl ammonium hydrogen sulfate (8.7 kg, 25.6mol) were added to the mixture. The mixture was refluxed for 10 hours togive the reaction mixture containing Compound (C).

Comparative Example 2

To the reaction mixture containing Compound (C) which was obtained inthe above Comparative Example 1 were added toluene (309.6 kg), Compound(D) (158.3 kg, 958.3 mol) and potassium carbonate (105.9 kg, 766.2 mol),and then the toluene (308 kg) was removed by heating. Then, the reactionmixture was cooled to 70° C. or lower, and water (5.7 kg) was added tothe mixture. The mixture was refluxed for 4 hours. The reaction mixturewas cooled, and water (2819 kg) was added to the mixture. The mixturewas separated with a separating funnel, and the toluene layer was washedwith 2.3% (w/w) brine (2466 kg). Further, active carbon (12.5 kg) wasadded to the toluene solution, and the mixture was stirred for 1 hour.The active carbon was removed by filtration and washed with toluene togive a toluene solution containing Compound (E) (2562 kg). The yield ofCompound (E) was 87.7% The yield of Compound (E) was calculated based onthe analytical result that the content of the compound in the toluenesolution was 10.8% (w/w) (which was calculated by LC absolutecalibration curve method). And, the production rate of by-product (R)was 9.83% (which was calculated with the above formula (a)).

Comparative Example 3

To a mixture of Compound (A) (90.0 kg, 410.4 mol), Compound (B) (147.9kg, 492.4 mol) and toluene (1460 kg) were added potassium carbonate(34.0 kg, 246.0 mol) and water (636 g), the toluene (298 kg) was removedby heating, and then the mixture was reflux-dehydrated for 34 hours.Then, the reaction mixture was cooled to 70° C. or lower, and potassiumcarbonate (17.0 kg, 123.0 mol) and tetra-n-butyl ammonium hydrogensulfate (5.6 kg, 16.5 mol) were added to the mixture. The mixture wasrefluxed for 12 hours to give the reaction mixture containing Compound(C). And, the production rate of by-product (R) was 3.02% (which wascalculated with the above formula (a)).

Comparative Example 4

To the reaction mixture containing Compound (C) which was obtained inthe above Comparative Example 3 were added toluene (198 kg), Compound(D) (101.7 kg, 615.7 mol) and potassium carbonate (68.1 kg, 492.7 mol),and then the toluene (198 kg) was removed by heating. Then, the reactionmixture was cooled to 70° C. or lower, and water (3.7 kg) was added tothe mixture. The mixture was refluxed for 3 hours. The reaction mixturewas cooled, and water (1803 kg) was added to the mixture. The mixturewas separated with a separating funnel, and the toluene layer was washedwith 2.3% (w/w) brine (1578 kg). Further, active carbon (8.0 kg) wasadded to the toluene solution, and the mixture was stirred for 1 hour.The active carbon was removed by filtration and washed with toluene togive a toluene solution containing Compound (E) (1625 kg). The yield ofCompound (E) was 90.1%. The yield of Compound (E) was calculated basedon the analytical result that the content of the compound in the toluenesolution was 11.2% (w/w) (which was calculated by LC absolutecalibration curve method). And, the production rate of by-product (R)was 3.08% (which was calculated with the above formula (a)).

Each reaction time, product yield, and by-product yield in the aboveexamples and comparative examples is shown in the following table.

By- By- Compound Inorganic Reaction Product product product (A) salttime yield (R) (6) Process (mol) (mol) (hr) (%) (%) (%) Example 1 (A)2.0 — 3 0.025 Example 2 (B) 1.2 94 0.12 — Example 3 (A) 2.0 0.18 13 0.31Example 4 (B) 2.0 93 1.21 0.10 Example 5 (A) 5.0 0.18 8 0.09 Example 6(B) 2.0 92 1.85 0.10 Example 7 (A) 1.8 0.18 24 1.28 Example 8 (B) 1.8 861.44 — Comparative (A) 0.83 0.75 15 — Example 1 Comparative (B) 1.0 889.83 — Example 2 Comparative (A) 0.83 0.75 46 3.02 Example 3 Comparative(B) 1.0 90 3.08 — Example 4 Process (A): Compound (A) + Compound (B) -->quaternary ammonium salt (C) Process (B): quaternary ammonium salt (C) +Compound (D) --> imide compound (E)

According to the results of Examples 1, 3, 5 and 7, the process of thepresent invention can make the reaction time for preparing quaternaryammonium salt (4) shortened, i.e. the reaction times in all the examplescould be steadily shortened in 24 hours. In addition, the transformationrate to Compound (1) in the reaction has been enhanced by the presentinvention. In particular, the transformation rates in Example 3, 5 and 7are about 100%, thus it is thought that the present invention hasindustrially excellent merits. Thereby, imide compound (8) could be alsoprepared in high yield in 2 steps via quaternary ammonium salt (4).Furthermore, the production of by-product (R) could be drastically helddown by the present invention. Accordingly, the process of the presentinvention is an industrially useful manufacturing method which is alsofor practical preparation.

Industrial Applicability

The process of the present invention is a process for preparingquaternary ammonium salt (4) in steady reaction time and in steadyquality, thus it has some merits, in particular for the industrialpurpose.

The invention claimed is:
 1. A process for preparing a quaternaryammonium salt of formula (4):

wherein X is halogen atom, C₁₋₆ alkylsulfonyloxy group, or C₆₋₁₀arylsulfonyloxy group, and X⁻ is a counteranion thereof, Y is asubstituent of the following formula (2a) or (2b):

wherein R¹ is independently methylene or oxygen atom; R² isindependently C₁₋₆ alkyl group, C₁₋₆ alkoxy group, or hydroxy group; mand n are independently 0, 1, 2, or 3; and p is 1 or 2, and Z is ═N—R³or ═CH—R⁴ wherein R³ is C₁₋₆ alkyl group, C₃₋₇ cycloalkyl group, C₅₋₇cycloalkenyl group, C₆₋₁₀ aryl group, or 5- to 10-membered monocyclic orbicyclic heteroaryl group; R⁴ is C₁₋₆ alkyl group, C₁₋₆ alkoxy group,C₁₋₆ alkylthio group, C₃₋₇ cycloalkyl group, C₃₋₇ cycloalkyloxy group,C₃₋₇ cycloalkylthio group, C₅₋₇ cycloalkenyl group, C₅₋₇ cycloalkenyloxygroup, C₅₋₇ cycloalkenylthio group, C₆₋₁₀ aryl group, C₆₋₁₀ aryloxygroup, C₆₋₁₀ arylthio group, 5- to 10-membered monocyclic or bicyclicheteroaryl group, 5- to 10-membered monocyclic or bicyclic heteroaryloxygroup, or 5- to 10-membered monocyclic or bicyclic heteroarylthio group,comprising reacting a compound of formula (1):

wherein X is independently selected from the above-defined ones, and Yis as defined above, with 1.8 to 15 mole of a compound of formula (3):

wherein Z is as defined above, per one mole of the compound of formula(1) to prepare the quaternary ammonium salt of formula (4).
 2. Theprocess of claim 1 wherein the reaction of Compound (1) with Compound(3) includes the following steps (i) and (ii): step (i): reactingCompound (1) with 0.1 to 1.0 mole of Compound (3) per one mole ofCompound (1), and then step (ii): adding the rest of Compound (3) to thereaction mixture so that the total amount of Compound (3) can be 1.8 to15 mole per one mole of Compound (1), and continuing the reaction. 3.The process of claim 1 wherein the reaction of Compound (1) withCompound (3) includes the following steps (i) and (ii): step (i):reacting 0.1 to 1.0 mole of Compound (1) with 0.1 to 1.0 mole ofCompound (3) per one mole of the total amount of Compound (1), and thenstep (ii): adding the rest of Compound (1) and the rest of Compound (3)to the reaction mixture so that the total amount of Compound (3) can be1.8 to 15 mole per one mole of the total amount of Compound (1), andcontinuing the reaction.
 4. The process of claim 2 wherein the reactionis carried out in the presence of 0.1 to 1.0 mole of solid inorganicbase per one mole of the total amount of Compound (1).
 5. The process ofclaim 4 wherein the solid inorganic base is potassium carbonate.
 6. Theprocess of claim 4 wherein the amount of an solid inorganic base is 0.1to 0.3 mole per one mole of the total amount of Compound (1).
 7. Theprocess of claim 2 wherein the amount of Compound (3) added in step (i)is 0.1 to 0.5 mole per one mole of the total amount of Compound (1). 8.The process of claim 2 wherein the total amount of Compound (3) in step(ii) is 1.8 to 5 mole per one mole of Compound (1).
 9. The process ofclaim 1 wherein X is independently C₁₋₆ alkylsulfonyloxy group, or C₆₋₁₀arylsulfonyloxy group.
 10. The process of claim 9 wherein X ismethanesulfonyloxy group.
 11. The process of claim 1 wherein Y is thesubstituent of formula (2a).
 12. The process of claim 11 wherein m is 2and n is
 0. 13. The process of claim 1 wherein Z is ═N—R³.
 14. Theprocess of claim 13 wherein R³ is 5- to 10-membered monocyclic orbicyclic heteroaryl group.
 15. The process of claim 14 wherein R³ is1,2-benzisothiazol-3-yl.
 16. A process for preparing a quaternaryammonium salt of formula (4a):

comprising reacting a compound of formula (1a):

with 1.8 to 15 mole of a compound of formula (3a):

per one mole of the compound of formula (1a) to prepare the quaternaryammonium salt of formula (4a).
 17. The process of claim 16 wherein thecompound of formula (1a) is